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Huang, J.* ; Sabater-Lleal, M.* ; Asselbergs, F.W.* ; Tregouet, D.* ; Shin, S.Y.* ; Ding, J.* ; Baumert, J.J. ; Oudot-Mellakh, T.* ; Folkersen, L.* ; Johnson, A.D.* ; Smith, N.L.* ; Williams, S.M.* ; Ikram, M.A.* ; Kleber, M.E.* ; Becker, D.M.* ; Truong, V.* ; Mychaleckyj, J.C.* ; Tang, W.* ; Yang, Q.* ; Sennblad, B.* ; Moore, J.H.* ; Williams, F.M.* ; Dehghan, A.* ; Silbernagel, G.* ; Schrijvers, E.M.* ; Smith, S.* ; Karakas, M.* ; Tofler, G.H.* ; Silveira, A.* ; Navis, G.J.* ; Lohman, K.* ; Chen, M.H.* ; Peters, A. ; Goel, A.* ; Hopewell, J.C.* ; Chambers, J.C.* ; Saleheen, D.* ; Lundmark, P.* ; Psaty, B.M.* ; Strawbridge, R.J.* ; Boehm, B.O.* ; Carter, A.M.* ; Meisinger, C. ; Peden, J.F.* ; Bis, J.C.* ; McKnight, B.* ; Ohrvik, J.* ; Taylor, K.* ; Franzosi, M.G.* ; Seedorf, U.* ; Collins, R.* ; Franco-Cereceda, A.* ; Syvanen, A.C.* ; Goodall, A.H.* ; Yanek, L.R.* ; Cushman, M.* ; Müller-Nurasyid, M. ; Folsom, A.R.* ; Basu, S.* ; Matijevic, N.* ; van Gilst, W.H.* ; Kooner, J.S.* ; Hofman, A.* ; Danesh, J.* ; Clarke, R.* ; Meigs, J.B.* ; DIAGRAM Consortium (Petersen, A.-K. ; Gieger, C. ; Klopp, N. ; Thorand, B. ; Grallert, H. ; Wichmann, H.-E. ; Illig, T. ; Meitinger, T. ; Huth, C.) ; Kathiresan, S.* ; Reilly, M.P.* ; CARDIoGRAM Consortium (Peters, A. ; Klopp, N. ; Wichmann, H.-E. ; Meisinger, C. ; Meitinger, T. ; Döring, A. ; Illig, T.) ; Harris, T.B.* ; Winkelmann, B.R.* ; Grant, P.J.* ; Hillege, H.L.* ; Watkins, H.* ; C4D Consortium (*) ; Spector, T.D.* ; Becker, L.C.* ; Tracy, R.P.* ; Marz, W.* ; Uitterlinden, A.G.* ; Eriksson, P.* ; Cambien, F.* ; CARDIOGENICS Consortium (*) ; Morange, P.E.* ; Koenig, W.* ; Soranzo, N.* ; van der Harst, P.* ; Liu, Y.* ; O'Donnell, C.J.* ; Hamsten, A.*

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.

Blood 120, 4873-4881 (2012)
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We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Plasminogen-activator Inhibitor-1 ; Coronary-artery-disease ; Myocardial-infarction ; Genetic-variation ; Susceptibility Loci ; Type-1 Expression ; Circadian Clock ; Plasma-levels ; Tissue ; Risk
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 120, Issue: 24, Pages: 4873-4881 Article Number: , Supplement: ,
Publisher American Society of Hematology
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Research Unit Molecular Epidemiology (AME)
POF-Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504000-002
G-504100-001
G-504200-001
PubMed ID 22990020
DOI 10.1182/blood-2012-06-436188
WOS ID WOS:000313115300031
Scopus ID 84870738355
Erfassungsdatum 2012-12-31
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